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Long-term outcomes for cryotherapy in Barrett’s esophagus with high-grade dysplasia: just cracking the ice
EDITORIAL
Long-term outcomes for cryotherapy in Barrett’s esophagus with high-grade dysplasia: just cracking the ice Although the progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) is well established, it has been increasingly recognized that there is an overall low frequency of this progression in the absence of dysplasia.1 Indeed, multiple, large population–based cohorts have demonstrated that the annual incidence of EAC in BE without dysplasia is 0.1% to 0.3% per year.1,2 In sharp contrast, the annual risk of progression to EAC in patients with high-grade dysplasia (HGD) is estimated at 6%.2 Given these epidemiologic findings and the considerable morbidity of surgical management of esophageal neoplasia, there has been sustained interest in the development and deployment of endoscopic therapy for BE with HGD including photodynamic therapy, radiofrequency ablation (RFA), cryotherapy, EMR, and endoscopic submucosal dissection (ESD). Currently, RFA is the most widely used and recommended endoscopic management technique for nonnodular BE with HGD, given the level 1 evidence (randomized, sham-controlled, and subsequent long-term follow-up) available for its efficacy in the eradication of intestinal metaplasia and dysplasia.3,4 This heat-based technique destroys mucosal tissue, with dosimetry titrated to limit the effects beyond the mucosa to deeper layers of the esophagus. Utilizing this technique, initial trials demonstrated complete eradication of dysplasia (CE-D) in 86% of patients and complete eradication of intestinal metaplasia (CE-IM) in 77%, with the incident development of EAC in only 1 patient.4 A subsequent meta-analysis of 18 studies confirmed similar rates of 91% CE-D and 78% CE-IM.5 For the management of nodular HGD or intramucosal carcinoma (ImCa), RFA is typically combined with EMR. A recent pooled analysis of 9 studies of combination therapy published in Gastrointestinal Endoscopy demonstrated a CE-D of 93.4% and CE-IM of 73.1%.6 The main drawback of this technique, however, is the development of treatment-associated strictures in approximately 5% of patients treated with RFA alone4,5,7 and in 10% to 13% of patients treated with RFA in combination with EMR.6,7 In this setting, cryoablation, either with liquid nitrogen or with carbon dioxide, has been explored as an alternative means of selective tissue ablation of IM with associated
dysplasia. Cryoablation is a noncontact method that consists of a directed spray of a cryogen, like liquid nitrogen ( 196 C), which causes rapid freezing and thawing. This process causes disruption of cell membranes, induces apoptosis, causes vascular ischemia, and causes thrombosis, resulting in the necrosis of superficial esophageal mucosal layers. In comparison with RFA, the tissue architecture of the superficial squamous layers is left relatively intact, and there is less tissue damage, which may underlie the reduced stricture formation rate with this modality. Several retrospective studies of cryotherapy have shown
More practical concerns, such as the considerable fixed costs associated with the purchase of RFA generators and catheters or the costs of having both RFA and cryotherapy systems available, may ultimately limit a single center’s ability to use these therapies on a case-by-case basis, choosing instead the best technology for the majority of patients.
Copyright ª 2017 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2017.03.1540
high rates of complete eradication of intestinal metaplasia and dysplasia, with minimal side effects.8 However, to date, there has been a lack of long-term data demonstrating the effectiveness of this therapy in eliminating HGD and IM. In this issue of Gastrointestinal Endoscopy, Ramay and colleagues9 present data on their single tertiary-care, referral center, retrospective study evaluating the 3-year and 5-year outcomes of liquid nitrogen spray cryotherapy (LNSCT) for the treatment of BE with HGD and ImCa. This experience represents an expansion of their previous publication of the 2-year follow-up of the same cohort.10 In the current study, the cohort consists of 50 patients followed up for 3 years and 40 patients followed up for 5 years of therapy and surveillance. Using LNSCT, the authors found initial rates of 98% (49/50) of patients with CE-HGD, 90% (45/50) of patients with CE-D, and 60% (30/50) of patients with CE-IM. At 3 years, among the 45 patients with initial CE-D, 24% (11/45) were noted to have dysplasia at follow-up, and among the 30 patients with initial CE-IM, 40% (12/30) were noted to have IM at follow-up. Recurrent dysplasia, which usually occurred
www.giejournal.org
Volume 86, No. 4 : 2017 GASTROINTESTINAL ENDOSCOPY 633
Editorial
Das & Falk
below the neosquamocolumnar junction, was able to be managed with retreatment in most cases. The authors examined durability (lack of a need for retreatment) at 5 years in their cohort of 40 patients, and they found that the durability of CE-HGD was 96%, of CE-D was 92%, and of CE-IM was 81%. Correspondingly, the incidence rates of recurrent IM, dysplasia, and HGD/EAC per person-year of follow-up after initial CE-IM were 12.2%, 4.0%, and 1.4% per person-year, respectively. There were 2 cases of incident EAC in this cohort, 1 of which developed during treatment and 1 that occurred 18 months after treatment with no reported mortality. Overall, Ramay and colleagues present important new information on the long-term durability of treatment of BE with HGD/ ImCa using LNSCT in their cohort with up to 5 years of follow-up. These data, however, must be examined in the context of the more robust body of literature on the use of RFA or multimodality EMR/RFA in the setting of treating BE with HGD or ImCa. A recent meta-analysis of RFA-based therapies found incidence rates of recurrent IM, dysplasia, and HGD/EAC per person-year of follow-up after initial CE-IM of 9.5%, 2.0%, and 1.2%, respectively, which is somewhat lower than the incidence of IM and dysplasia in the current study.11 While these results are not directly comparable, given the heterogeneity of the studies included in the meta-analysis and its much larger overall sample size, this prompts a fundamental question about the treatment of BE: is the objective to remove dysplasia and/or carcinoma or to eradicate IM itself in conjunction with antisecretory therapies? Given our expanding knowledge of the pathogenesis of the metaplasia-to-dysplasia pathway, only with the total elimination of IM itself could one expect to break this cycle. Furthermore, given the increased demands for cost-effective treatments, the enormous number of patients with recognized and unrecognized BE, and the demands on the health care system for ongoing surveillance after endoscopic intervention, one may make an argument that an ideal therapy for dysplastic BE is one that (1) achieves CE-IM most durably and (2) does so in as few treatments as possible. As LNSCT comes of age in an era of mature, long-term data on the efficacy of RFAbased treatment regimens, LNSCT will inherently have to be judged against this benchmark. Several questions emerge in evaluating the wider use of the LNSCT technology. Dosimetry is of particular importance, inasmuch as one of the primary limitations of the therapy is the depth of tissue necrosis achieved. The depth and extent of cellular destruction is proportional to the number of freeze-thaw cycles, the duration of the freezing, and the distance from the cryogen.12 Based on data from swine models, cryotherapy-induced tissue destruction may range from superficial mucosal inflammation to transmural necrosis, depending on the cycle time.12 In addition to the cycles, an equal distribution of the cryogen must be made onto the esophageal mucosa, which is often
variegated or irregular. The authors in the current study make a point that dosimetry was “changed over time based on clinical experience and dosimetry studies,” and indeed they describe 3 different protocols (3 cycles of 20 seconds, 4 cycles of 10 seconds, 2 cycles of 20 seconds) that were used over the 5-year period. Although this reflects a real-world adaptation, the variations in technique constitute a factor that requires further study because it inherently will affect the depth of treatment and presumably the durability of clinical response. This variability in dosimetry, in contrast to the fixed and reproducible dosimetry delivered by RFA, remains a consistent problem in the cryotherapy literature. Perhaps the largest question is how this technology will integrate into clinical use. Although careful examination of multiple prospective and retrospective series have demonstrated the superiority of EMR for the management of nodular dysplasia and RFA for the management of flat dysplasia, and their combination to be superior to the use of sequential EMR for the management of BE with HGD,6 this level of data is lacking for LNSCT in conjunction with these existing technologies. There may be unique scenarios, for example in patients with recalcitrant strictures after RFA/EMR or other anatomic deformities of the esophagus that make radiofrequency probe contact problematic, wherein LNSCT may be uniquely suited. However, more practical concerns, such as the considerable fixed costs associated with the purchase of RFA generators and catheters or the costs of having both RFA and cryotherapy systems available, may ultimately limit a single center’s ability to use these therapies on a case-by-case basis, choosing instead the best technology for the majority of patients. Irrespective, as more data become available on the long-term outcomes of LNSCT, delineating the role of this technology in the context of RFA/EMR warrants Markov modeling and, ultimately, randomized head-to-head trials with specific algorithmic treatment protocols for patients with BE.
634 GASTROINTESTINAL ENDOSCOPY Volume 86, No. 4 : 2017
www.giejournal.org
DISCLOSURE All authors disclosed no financial relationships relevant to this publication. Koushik K. Das, MD Division of Gastroenterology Department of Medicine Washington University School of Medicine St. Louis, Missouri, USA Gary W. Falk, MD, MS Division of Gastroenterology Department of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania, USA
Das & Falk
Editorial
Abbreviations: BE, Barrett’s esophagus; CE-D, complete eradication of dysplasia; CE-IM, complete eradication of intestinal metaplasia; EAC, esophageal adenocarcinoma; ESD, endoscopic submucosal dissection; HGD, high-grade dysplasia; ImCA, intramucosal carcinoma; LNSCT, liquid nitrogen spray cryotherapy; RFA, radiofrequency ablation.
REFERENCES 1. Wani S, Falk G, Hall M, et al. Patients with nondysplastic Barrett’s esophagus have low risks for developing dysplasia or esophageal adenocarcinoma. Clin Gastroenterol Hepatol 2011;9:220-7; quiz e26. 2. Spechler SJ. Barrett esophagus and risk of esophageal cancer: a clinical review. JAMA 2013;310:627-36. 3. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med 2009;360:2277-88. 4. Shaheen NJ, Overholt BF, Sampliner RE, et al. Durability of radiofrequency ablation in Barrett’s esophagus with dysplasia. Gastroenterology 2011;141:460-8. 5. Orman ES, Li N, Shaheen NJ. Efficacy and durability of radiofrequency ablation for Barrett’s esophagus: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2013;11:1245-55.
6. Desai M, Saligram S, Gupta N, et al. Efficacy and safety outcomes of multimodal endoscopic eradication therapy in Barrett’s esophagusrelated neoplasia: a systematic review and pooled analysis. Gastrointest Endosc 2017;85:482-4. 7. Qumseya BJ, Wani S, Desai M, et al. Adverse events after radiofrequency ablation in patients with Barrett’s esophagus: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2016;14 1086-6. 8. Ghorbani S, Tsai FC, Greenwald BD, et al. Safety and efficacy of endoscopic spray cryotherapy for Barrett’s dysplasia: results of the National Cryospray Registry. Dis Esophagus 2016;29:241-7. 9. Ramay FH, Cui Q, Greenwald BD. Outcomes after liquid nitrogen spray cryotherapy in Barrett’s esophagus–associated high-grade dysplasia and intramucosal adenocarcinoma: 5-year follow-up. Gastrointest Endosc 2017;86:626-32. 10. Halsey KD, Chang JW, Waldt A, et al. Recurrent disease following endoscopic ablation of Barrett’s high-grade dysplasia with spray cryotherapy. Endoscopy 2011;43:844-8. 11. Krishnamoorthi R, Singh S, Ragunathan K, et al. Risk of recurrence of Barrett’s esophagus after successful endoscopic therapy. Gastrointest Endosc 2016;83:1090-3. 12. Raju GS, Ahmed I, Xiao SY, et al. Graded esophageal mucosal ablation with cryotherapy, and the protective effects of submucosal saline. Endoscopy 2005;37:523-6.
GIE on LinkedIn Follow GIE on LinkedIn. Followers will receive news, updates, and links to author interviews, podcasts, articles, and tables of contents. Search on LinkedIn for “GIE: Gastrointestinal Endoscopy with Editor Michael B. Wallace” and follow us today.
www.giejournal.org
Volume 86, No. 4 : 2017 GASTROINTESTINAL ENDOSCOPY 635
Long-term outcomes for cryotherapy in Barrett’s esophagus with high-grade dysplasia: just cracking the ice Although the progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) is well established, it has been increasingly recognized that there is an overall low frequency of this progression in the absence of dysplasia.1 Indeed, multiple, large population–based cohorts have demonstrated that the annual incidence of EAC in BE without dysplasia is 0.1% to 0.3% per year.1,2 In sharp contrast, the annual risk of progression to EAC in patients with high-grade dysplasia (HGD) is estimated at 6%.2 Given these epidemiologic findings and the considerable morbidity of surgical management of esophageal neoplasia, there has been sustained interest in the development and deployment of endoscopic therapy for BE with HGD including photodynamic therapy, radiofrequency ablation (RFA), cryotherapy, EMR, and endoscopic submucosal dissection (ESD). Currently, RFA is the most widely used and recommended endoscopic management technique for nonnodular BE with HGD, given the level 1 evidence (randomized, sham-controlled, and subsequent long-term follow-up) available for its efficacy in the eradication of intestinal metaplasia and dysplasia.3,4 This heat-based technique destroys mucosal tissue, with dosimetry titrated to limit the effects beyond the mucosa to deeper layers of the esophagus. Utilizing this technique, initial trials demonstrated complete eradication of dysplasia (CE-D) in 86% of patients and complete eradication of intestinal metaplasia (CE-IM) in 77%, with the incident development of EAC in only 1 patient.4 A subsequent meta-analysis of 18 studies confirmed similar rates of 91% CE-D and 78% CE-IM.5 For the management of nodular HGD or intramucosal carcinoma (ImCa), RFA is typically combined with EMR. A recent pooled analysis of 9 studies of combination therapy published in Gastrointestinal Endoscopy demonstrated a CE-D of 93.4% and CE-IM of 73.1%.6 The main drawback of this technique, however, is the development of treatment-associated strictures in approximately 5% of patients treated with RFA alone4,5,7 and in 10% to 13% of patients treated with RFA in combination with EMR.6,7 In this setting, cryoablation, either with liquid nitrogen or with carbon dioxide, has been explored as an alternative means of selective tissue ablation of IM with associated
dysplasia. Cryoablation is a noncontact method that consists of a directed spray of a cryogen, like liquid nitrogen ( 196 C), which causes rapid freezing and thawing. This process causes disruption of cell membranes, induces apoptosis, causes vascular ischemia, and causes thrombosis, resulting in the necrosis of superficial esophageal mucosal layers. In comparison with RFA, the tissue architecture of the superficial squamous layers is left relatively intact, and there is less tissue damage, which may underlie the reduced stricture formation rate with this modality. Several retrospective studies of cryotherapy have shown
More practical concerns, such as the considerable fixed costs associated with the purchase of RFA generators and catheters or the costs of having both RFA and cryotherapy systems available, may ultimately limit a single center’s ability to use these therapies on a case-by-case basis, choosing instead the best technology for the majority of patients.
Copyright ª 2017 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2017.03.1540
high rates of complete eradication of intestinal metaplasia and dysplasia, with minimal side effects.8 However, to date, there has been a lack of long-term data demonstrating the effectiveness of this therapy in eliminating HGD and IM. In this issue of Gastrointestinal Endoscopy, Ramay and colleagues9 present data on their single tertiary-care, referral center, retrospective study evaluating the 3-year and 5-year outcomes of liquid nitrogen spray cryotherapy (LNSCT) for the treatment of BE with HGD and ImCa. This experience represents an expansion of their previous publication of the 2-year follow-up of the same cohort.10 In the current study, the cohort consists of 50 patients followed up for 3 years and 40 patients followed up for 5 years of therapy and surveillance. Using LNSCT, the authors found initial rates of 98% (49/50) of patients with CE-HGD, 90% (45/50) of patients with CE-D, and 60% (30/50) of patients with CE-IM. At 3 years, among the 45 patients with initial CE-D, 24% (11/45) were noted to have dysplasia at follow-up, and among the 30 patients with initial CE-IM, 40% (12/30) were noted to have IM at follow-up. Recurrent dysplasia, which usually occurred
www.giejournal.org
Volume 86, No. 4 : 2017 GASTROINTESTINAL ENDOSCOPY 633
Editorial
Das & Falk
below the neosquamocolumnar junction, was able to be managed with retreatment in most cases. The authors examined durability (lack of a need for retreatment) at 5 years in their cohort of 40 patients, and they found that the durability of CE-HGD was 96%, of CE-D was 92%, and of CE-IM was 81%. Correspondingly, the incidence rates of recurrent IM, dysplasia, and HGD/EAC per person-year of follow-up after initial CE-IM were 12.2%, 4.0%, and 1.4% per person-year, respectively. There were 2 cases of incident EAC in this cohort, 1 of which developed during treatment and 1 that occurred 18 months after treatment with no reported mortality. Overall, Ramay and colleagues present important new information on the long-term durability of treatment of BE with HGD/ ImCa using LNSCT in their cohort with up to 5 years of follow-up. These data, however, must be examined in the context of the more robust body of literature on the use of RFA or multimodality EMR/RFA in the setting of treating BE with HGD or ImCa. A recent meta-analysis of RFA-based therapies found incidence rates of recurrent IM, dysplasia, and HGD/EAC per person-year of follow-up after initial CE-IM of 9.5%, 2.0%, and 1.2%, respectively, which is somewhat lower than the incidence of IM and dysplasia in the current study.11 While these results are not directly comparable, given the heterogeneity of the studies included in the meta-analysis and its much larger overall sample size, this prompts a fundamental question about the treatment of BE: is the objective to remove dysplasia and/or carcinoma or to eradicate IM itself in conjunction with antisecretory therapies? Given our expanding knowledge of the pathogenesis of the metaplasia-to-dysplasia pathway, only with the total elimination of IM itself could one expect to break this cycle. Furthermore, given the increased demands for cost-effective treatments, the enormous number of patients with recognized and unrecognized BE, and the demands on the health care system for ongoing surveillance after endoscopic intervention, one may make an argument that an ideal therapy for dysplastic BE is one that (1) achieves CE-IM most durably and (2) does so in as few treatments as possible. As LNSCT comes of age in an era of mature, long-term data on the efficacy of RFAbased treatment regimens, LNSCT will inherently have to be judged against this benchmark. Several questions emerge in evaluating the wider use of the LNSCT technology. Dosimetry is of particular importance, inasmuch as one of the primary limitations of the therapy is the depth of tissue necrosis achieved. The depth and extent of cellular destruction is proportional to the number of freeze-thaw cycles, the duration of the freezing, and the distance from the cryogen.12 Based on data from swine models, cryotherapy-induced tissue destruction may range from superficial mucosal inflammation to transmural necrosis, depending on the cycle time.12 In addition to the cycles, an equal distribution of the cryogen must be made onto the esophageal mucosa, which is often
variegated or irregular. The authors in the current study make a point that dosimetry was “changed over time based on clinical experience and dosimetry studies,” and indeed they describe 3 different protocols (3 cycles of 20 seconds, 4 cycles of 10 seconds, 2 cycles of 20 seconds) that were used over the 5-year period. Although this reflects a real-world adaptation, the variations in technique constitute a factor that requires further study because it inherently will affect the depth of treatment and presumably the durability of clinical response. This variability in dosimetry, in contrast to the fixed and reproducible dosimetry delivered by RFA, remains a consistent problem in the cryotherapy literature. Perhaps the largest question is how this technology will integrate into clinical use. Although careful examination of multiple prospective and retrospective series have demonstrated the superiority of EMR for the management of nodular dysplasia and RFA for the management of flat dysplasia, and their combination to be superior to the use of sequential EMR for the management of BE with HGD,6 this level of data is lacking for LNSCT in conjunction with these existing technologies. There may be unique scenarios, for example in patients with recalcitrant strictures after RFA/EMR or other anatomic deformities of the esophagus that make radiofrequency probe contact problematic, wherein LNSCT may be uniquely suited. However, more practical concerns, such as the considerable fixed costs associated with the purchase of RFA generators and catheters or the costs of having both RFA and cryotherapy systems available, may ultimately limit a single center’s ability to use these therapies on a case-by-case basis, choosing instead the best technology for the majority of patients. Irrespective, as more data become available on the long-term outcomes of LNSCT, delineating the role of this technology in the context of RFA/EMR warrants Markov modeling and, ultimately, randomized head-to-head trials with specific algorithmic treatment protocols for patients with BE.
634 GASTROINTESTINAL ENDOSCOPY Volume 86, No. 4 : 2017
www.giejournal.org
DISCLOSURE All authors disclosed no financial relationships relevant to this publication. Koushik K. Das, MD Division of Gastroenterology Department of Medicine Washington University School of Medicine St. Louis, Missouri, USA Gary W. Falk, MD, MS Division of Gastroenterology Department of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania, USA
Das & Falk
Editorial
Abbreviations: BE, Barrett’s esophagus; CE-D, complete eradication of dysplasia; CE-IM, complete eradication of intestinal metaplasia; EAC, esophageal adenocarcinoma; ESD, endoscopic submucosal dissection; HGD, high-grade dysplasia; ImCA, intramucosal carcinoma; LNSCT, liquid nitrogen spray cryotherapy; RFA, radiofrequency ablation.
REFERENCES 1. Wani S, Falk G, Hall M, et al. Patients with nondysplastic Barrett’s esophagus have low risks for developing dysplasia or esophageal adenocarcinoma. Clin Gastroenterol Hepatol 2011;9:220-7; quiz e26. 2. Spechler SJ. Barrett esophagus and risk of esophageal cancer: a clinical review. JAMA 2013;310:627-36. 3. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med 2009;360:2277-88. 4. Shaheen NJ, Overholt BF, Sampliner RE, et al. Durability of radiofrequency ablation in Barrett’s esophagus with dysplasia. Gastroenterology 2011;141:460-8. 5. Orman ES, Li N, Shaheen NJ. Efficacy and durability of radiofrequency ablation for Barrett’s esophagus: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2013;11:1245-55.
6. Desai M, Saligram S, Gupta N, et al. Efficacy and safety outcomes of multimodal endoscopic eradication therapy in Barrett’s esophagusrelated neoplasia: a systematic review and pooled analysis. Gastrointest Endosc 2017;85:482-4. 7. Qumseya BJ, Wani S, Desai M, et al. Adverse events after radiofrequency ablation in patients with Barrett’s esophagus: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2016;14 1086-6. 8. Ghorbani S, Tsai FC, Greenwald BD, et al. Safety and efficacy of endoscopic spray cryotherapy for Barrett’s dysplasia: results of the National Cryospray Registry. Dis Esophagus 2016;29:241-7. 9. Ramay FH, Cui Q, Greenwald BD. Outcomes after liquid nitrogen spray cryotherapy in Barrett’s esophagus–associated high-grade dysplasia and intramucosal adenocarcinoma: 5-year follow-up. Gastrointest Endosc 2017;86:626-32. 10. Halsey KD, Chang JW, Waldt A, et al. Recurrent disease following endoscopic ablation of Barrett’s high-grade dysplasia with spray cryotherapy. Endoscopy 2011;43:844-8. 11. Krishnamoorthi R, Singh S, Ragunathan K, et al. Risk of recurrence of Barrett’s esophagus after successful endoscopic therapy. Gastrointest Endosc 2016;83:1090-3. 12. Raju GS, Ahmed I, Xiao SY, et al. Graded esophageal mucosal ablation with cryotherapy, and the protective effects of submucosal saline. Endoscopy 2005;37:523-6.
GIE on LinkedIn Follow GIE on LinkedIn. Followers will receive news, updates, and links to author interviews, podcasts, articles, and tables of contents. Search on LinkedIn for “GIE: Gastrointestinal Endoscopy with Editor Michael B. Wallace” and follow us today.
www.giejournal.org
Volume 86, No. 4 : 2017 GASTROINTESTINAL ENDOSCOPY 635